Control release of fat soluable antioxidants from an oral formulation and method

ABSTRACT

Oral formulation of particles made of an agglomeration of a plurality of seed granules or a single seed granule both surrounded by three layers and an outer gel coating. The seed granules are made of calcium carbonate with microscopic fissures. Disposed inside the fissures and in the interstitial spaces of the agglomerate seed granules are microscopic particles of alkali metal salts and other ions. Coating the agglomerate or single seed granules is an alkaline-resistant first layer made of microcrystalline cellulose and croscarmellose sodium that binds and protects the surrounding second layer. Surrounding the second layer is a third layer made of alkaline earth metal salt particles holding alkali metal hydroxide ions within a polysaccharide or polymer gel. Surrounding the third layer is at least one outer gel layer. The fourth and third layers dissolve in a low pH environment and release the fat soluble antioxidant and ions in the seed granule fissures.

This utility patent application is based on and claims the filing datebenefit of U.S. provisional patent application (62/149,063) filed onApr. 17, 2015.

Notice is given that the following patent document contains originalmaterial subject to copyright protection. The copyright owner has noobjection to the facsimile or digital download reproduction of all orpart of the patent document, but otherwise reserves all copyrights.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to control release of ingredients in oralformulations and more particularly to the control release of fat solubleantioxidants including but not limited to flavonoids in oralformulations.

2. Description of the Related Art

Fat soluble antioxidants are defined here as phenolic or polyphenolicphytochemicals with low solubility in water and neutralize oxygen freeradicals in vitro. They include vitamin E, ellagic acid, curcumin,capsaicin and the flavonoid family of compounds. Flavonoids are a classof plant metabolites with a general structure of a 15-carbon skeleton,which comprises two phenyl rings and a heterocyclic ring. The presentinvention includes phytonutrient flavonoids and certain derivativeshaving a general structure of a 14- to 30-carbon skeleton, whichcomprises two phenyl rings (referred to as “fat soluble antioxidants” or“FSA”).

Fat soluble antioxidants are part of the human diet and are foundubiquitously in plants. Their wide distribution, variety and lowtoxicity mean that many animals, including humans, ingest significantquantities in their diet. Dietary sources of fat soluble antioxidants,such as flavonoids are well documented.

In vitro studies have shown flavonoids to have a wide range ofbiological and pharmacological activities. Examples includeanti-inflammatory, antioxidant, capillary vein rebuilding, antimicrobialand antiviral activities.

Flavonoids are effective scavengers of free radicals in the test tube(in vitro) and an excellent scavenger of most Reactive Oxygen Species(“ROS”). With their level of reactivity, not surprisingly, flavonoidsdegrade when exposed to light and oxygen during storage and cooking, anddegrade with enzymes and acids during digestion.

Flavonoids are fat soluble and are insoluble in water. Absorption in theGI tract is low as is flavonoid bioavailability. New formulations offlavonoid delivery systems focus on biocompatible organic substanceslike liposomes, polyethylene glycols, biopolymers, cellulose, corn oiland hydrogels chemically attached to the flavonoid.

Other attempts to improve flavonoid absorption involve attachingflavonoid to lipids, liposomes, albumins, cyclodextrin, cucurbituryl,surfactants, and natural and synthetic polymers.

Research at the Linus Pauling Institute and the European Food SafetyAuthority shows that flavonoids are poorly absorbed in the human body(less than 5%), with most of what is absorbed being metabolized andexcreted.

There is, accordingly, an ongoing need in the art for a general deliveryformulation that allows fat soluble antioxidants, such as flavonoids, tosurvive storage and digestive processes until the fat solubleanti-oxidant can be released in full potency when the desiredpharmacokinetic conditions are present (typically in the upperintestinal tract) and to coincidentally release molecules in the GItract to aid in the absorption of the fat soluble antioxidant across theintestinal lumen and villi.

An ideal formulation would protect the fat soluble antioxidant fromlight, air, abrasion or chemical interaction under normal conditions;extend shelf-life for fat soluble antioxidant based products; andprotect the fat soluble antioxidant for up to twenty (20) minutes afteringestion so the fat soluble antioxidant safely passes through thehighly acidic, enzyme-active stomach intact; and releases the fatsoluble antioxidant directly into the gut coincidentally with moleculesto aid in flavonoid absorption through the lumen mucous membrane andvilli to pass into the blood stream or into the lymphatic system.

SUMMARY OF THE INVENTION

A controlled release oral formulation containing a fat solubleantioxidant layer containing one or more fat soluble antioxidants(hereinafter aka “FSA”). The oral formulation is made of two types ofparticles. One particle made up on a plurality of seed granules (calleda seed granule agglomerate and known as a Type 1 seed granule) boundtogether and the other particle made up of a single seed granule, (knownas a Type 2 seed granule). The seed granules are made of microscopic(0.5 μm to 20 μm) alkaline earth metal crystal and include microscopicfissures formed therein Disposed inside the microscopic fissures aremicroscopic particles of alkali metal salt, alkali metal hydroxide orother ions. Disposed in the interstitial spaces between the seedgranules in the Type 1 particles are also microscopic particles ofalkali metal salt, alkali metal hydroxide and other ions.

Coating the seed granule agglomerate and the single seed granule is afirst layer made of microcrystalline cellulose (“MCC”) and/orcroscarmellose sodium that is alkaline-resistant and binds to the seedgranule. Surrounding the first layer is a second layer made of a fatsoluble antioxidant mixture. The first layer separates the highlyreactive seed granules from a surrounding second layer made of a fatsoluble antioxidant mixture.

Surrounding the FSA second layer is a third layer made of microscopicalkaline earth metal salt particles in a mixture holding microscopicalkali metal hydroxide ions in fissures and interstitial spaces within apolysaccharide or polymer gel. The third layer is configured to protectthe fat soluble antioxidant in the second layer from the atmosphere andlight and protect the fat soluble antioxidant from enzymes and acids inthe stomach for a period of to 20 to 30 minutes. Surrounding the thirdlayer is at least one outer layer made of hardened, thermo-sensitivepolymer gel, (preferably hydroxypropyl methylcellulose aka “HPMC”).

When the particles are exposed to a low pH environment in the stomach,the third and fourth layers slowly dissolve. The second layer made offat soluble antioxidant mixture is exposed. When the particles pass intothe small intestine with a high pH environment, the second layer andthen the first layers sequentially disperse and dissolve releasing thefat soluble antioxidant and the ions in the interstitial spaces andfissures of the seed granules. It is postulated that ions in the seedgranules are released to open ion channels in the small intestineallowing more fat soluble antioxidant to be absorbed.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a Type 1 seed granule made of a pluralityof microscopic alkaline earth metal carbonate crystals with interstitialspaces and fissures.

FIG. 2 is an illustration of an irregular shaped Type 2 seed granulemade of a single alkaline earth metal carbonate with a plurality offissures.

FIG. 3 is a sectional, side elevational view of the seed granule shownin FIG. 2.

FIG. 4 is an illustration showing the first layer containing MCCsurrounding the seed granule.

FIG. 5 is a sectional, side elevational view of the seed granule coveredby the first layer as shown in FIG. 4.

FIG. 6 is an illustration showing the second layer containing a fatsoluble anti-oxidant (flavonoids) surrounding the first layer containingMCC that surrounds the seed granule.

FIG. 7 is a sectional, side elevational view of the seed granule coveredby the second and first layers shown in FIG. 6.

FIG. 8 is an illustration showing the third layer containing Type 1granules of CaCO3 with alkali metal hydroxides surrounding the secondlayer containing a fat soluble anti-oxidant (flavonoids) that surroundsthe first layer containing MCC and surrounds the seed granule.

FIG. 9 is an illustration showing the fourth layer containing HPMC gelthat surrounds the third layer containing CaCO3 with alkali metalhydroxide, an inner second layer containing a fat soluble anti-oxidant,and inner first layer containing MCC that surrounds the seed granule.

FIG. 10 is a graph showing the dissolution rate and acid neutralizingeffect of layer 3 and layer 4 of a particle over time in 2.0 pH HCl tosimulate stomach acid.

FIG. 11 is a graph showing the dissolution rate of Diosmin (a type ofFSA) over time as it disperses and dissolves into solution aftersurviving 2.0 pH HCl for 20 minutes.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S) I. Definitions andNomenclature

Unless defined otherwise, all technical and scientific terms used havethe meaning commonly understood by one of ordinary skill in the art towhich the invention pertains. Specific terminology of particularimportance to the description of the present invention is defined below.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context dictatesotherwise. For example, “the flavonoid” may refer to a mixture ofseveral compatible flavonoids that comprise a component of the finishedcomposition.

As used, “subject” or “individual” or “patient” refers to any subjectfor whom or which therapy is desired, and refers to the recipient of thetherapy to be practiced according to the invention. The subject can bemale or female.

As used, “fat soluble antioxidants” or “FSA” are phenolic orpolyphenolic phytochemicals with low solubility in water and neutralizeoxygen free radicals in vitro. They include vitamin E, ellagic acid,curcumin, capsaicin and the flavonoid family of compounds. Flavonoidsare a class of plant metabolites with a general structure of a 15-carbonskeleton, which comprises two phenyl rings and a heterocyclic ring. Fatsoluble antioxidants include phytonutrients having a general structureof a 14- to 30-carbon skeleton, which comprises two phenyl rings andtheir metabolites whether they be free or held in lipids, liposomes,albumins, cyclodextrin, cucurbituryl, surfactants, and polymers.

II. Sustained Release Fat Soluble Antioxidant Particles

a. General Description:

The sustained release fat soluble antioxidant particles are composed ofan inner seed granule surrounded by three (3) layers and at least oneouter gel layer.

There are two types of particles: Type 1 and Type 2. A Type 1 particleis made of a plurality of seed granules each made of microscopic (0.5 μmto 20 μm) alkaline earth metal salt crystals (preferably calciumcarbonate) containing fissures on the face of the crystal andagglomerated using microcrystalline cellulose (“MCC”) and/orcroscarmellose sodium. A Type 2 particle is a single seed granule madeof single alkaline earth metal salt crystal (preferably calciumcarbonate) containing microscopic fissures. Disposed in the interstitialspace of Type 1 and in the microscopic fissures of Type 1 and Type 2seed granule are microscopic particles of alkali metal salt, alkalimetal hydroxide and/or other ions.

The first layer surrounds the seed granule and is made of pH neutralexcipients that protect and shield the seed granule from the secondlayer containing a fat soluble antioxidant.

The fat soluble antioxidant material in the second layer is held in apolymer matrix and surrounds the first layer;

A third layer contains a fine mixture of microscopic alkaline earthmetal crystals containing fissures and interstitial spaces. Inside thefissures and interstitial spaces are particles of alkali earth metalhydroxide held with pH neutral excipients in a polysaccharide or polymergel. The selection and use of the polysaccharide or polymer gel holdingthe fine mixture of agglomerated alkaline earth metal crystals dependson the characteristics of the second layer fat soluble antioxidant.

One or more outer gel layers containing a thermal-sensitive polymer(preferably hydroxypropyl methylcellulose or HPMC) are heatedsufficiently to form a protective gelation around the third layer tocomplete the coating process.

The resulting particles are sized with shape and surface area effectiveto permit easy pressing as tablets and filling in capsules, gel caps andother oral delivery systems typically no larger than 800 μm.

b. Granule Components:

Each seed granule is made of alkaline earth metal salt crystals(preferably calcium carbonate) with a low solubility in water and a highdegree of fissuring on the face of the crystal. There are two types ofseed granules: seed granules known as Type 1 seed granules are made of aplurality of microscopic seed granules crystals agglomerated and boundwith microcrystalline cellulose (MCC) and croscarmellose sodium or asingle granule crystal known as Type 2. Disposed within the fissures andinterstitial space of the Type 1 seed granules or the fissures of theType 2 seed granule are alkali metal salt crystals (such as potassiumhydroxide, potassium chloride and sodium hydroxide) with high solubilityin water plus other ionic molecules with similar characteristics thatmay assist in absorption in the GI tract. The components which easilyionized in water are mixed with the other components in a shear mixerextensively with appropriate diffused liquid so the alkali metal saltsand similar molecules (typically in ionic form) reside within fissuresand interstitial spaces of the seed granules.

The first layer surrounding the seed granule agglomerate or the singleseed granule is made of one or more alkaline-resistant excipients thatdissolve easily in an aqueous liquid medium but withstand high pHwithout degradation or reaction (like microcrystalline cellulose andcroscarmellose sodium) and dried to 3% to 7% moisture content to seal inthe highly reactive alkali metal salts in the seed granule.

The second layer is a mixture of fat soluble antioxidants. In theembodiment presented the fat soluble antioxidant is a flavonoid. Theflavonoid is suspended in a non-reactive polysaccharide or a polymer geland dried.

The third layer is made of microscopic (0.5 μm to 20 μm) alkaline earthmetal salt crystals (preferably calcium carbonate) with low solubilityin water and a plurality of fissures on the face of the alkaline earthmetal salt crystals. The microscopic alkaline earth mineral saltcrystals may be agglomerated to create interstitial spaces between thecrystals. If agglomerated, the binding material will be microcrystallinecellulose (MCC) and/or croscarmellose sodium. Inside the fissures andinterstitial spaces between the alkaline earth salt crystals are alkalimetal salt crystals with high pH characteristics (preferably potassiumhydroxide and/or sodium hydroxide) with high solubility in water. Thethird layer may also use a non-reactive poly saccharide or polymer gelas a binder to connect the third layer with the second layer dependingon the second layer fat soluble antioxidant. The third layer is dried to3% to 7% moisture content to seal in the highly reactive alkali metalsalts.

One or more outer layers form an outer cover for the third layer andcomprise one or more coatings with a thermal-sensitive polymer gel(typically preferably hydroxypropyl methylcellulose or HPMC) that isnon-reactive with anti-oxidants and can withstand a wide range of pHlevels without rapid deterioration.

The finished particle is sized to have a size, shape, and surface areaeffective to permit easy pressing as tablets and filling in capsules,gel caps and other oral delivery systems.

c. Size, Shape, Surface Area Volume Ratio and/or Weight Ratio forVarious Layers That Comprise the Particle:

Seed granule agglomerate used in the Type 1 particle is made of aplurality of seed granules that measure approximately (0.5 μm to 20 μm)in size and made of alkaline earth metal salt crystals. When bounded,the seed granule agglomerate is irregularly shaped between 50 μm and 500μm in the longest dimension. The single seed granule is also irregularlyshaped between 100 μm and 500 μm in its longest dimension with a lowsolubility in water. The alkaline earth metal salt crystals are selectedfor the high surface area offered by fissures on the face of thecrystals. Located inside the fissures of each single seed granule andinside the fissures and interstitial space of the seed granules used inthe seed granules agglomerate are alkali metal salt crystals in ionicform (such as potassium hydroxide, potassium chloride and/or sodiumhydroxide) with high solubility in water amounting to 3% to 7% of theseed granule's mass (exclusive of binders). Also inside the fissures ofthe single seed granule and the fissures and interstitial spaces of seedgranule agglomerates may be other ionic molecules with similar physicalcharacteristics that may assist in absorption in the GI tract amountingto 0% to 10% of the seed granule mass (exclusive of binders). The seedgranule mass is between 10% to 20% of the finished particle mass.

The first layer comprises one or more alkaline-resistant excipients thatdissolve easily in a aqueous liquid medium but withstand high pH withoutdegradation or reaction (like microcrystalline cellulose andcroscarmellose sodium) and dried to 3% to 7% moisture content and is upto 5 μm in thickness and comprises a negligible mass in the finishedgranule. The second layer comprising a mixture of fat solubleantioxidant material suspended in a non-reactive polysaccharide or apolymer gel is dried to form a layer of one or more fat solubleantioxidants in an unaltered condition 15 μm to 100 μm thick and equalto 100% to 300% of the volume of the seed granule and 15% to 40% of thefinished particle mass.

The third layer is made of small (0.5 μm to 20 μm) alkaline earth metalsalt crystals (preferably calcium carbonate) with a low solubility inwater and significant fissuring on the face of the crystals. Thealkaline earth metal crystals equal 90% to 95% of the layer #3 mass(exclusive of binders). The balance of the third layer mass (exclusiveof binders) are alkali metal salt crystals with high pH characteristics(preferably potassium hydroxide and sodium hydroxide). Sufficientdiffused water is mixed with the alkali metal salt crystals and thealkaline earth metal crystals so the alkali metal salt crystals(typically in ionic form) reside within fissures of the alkali earthmetal salt crystals and are bound with one or more alkaline-resistantexcipients that dissolve easily in a aqueous liquid medium but withstandhigh pH without degradation or reaction (like microcrystalline celluloseand croscarmellose sodium). The third layer is dried to 3% to 7%moisture content so the third layer surrounds the second layer with acovering 20 μm to 200 μm thick and may comprise 15% to 30% of the massof the finished particle.

The fourth layer comprises one or more coatings with a thermo-sensitivepolymer gel (typically preferably hydroxypropyl methylcellulose) that isnon-reactive with anti-oxidants and can withstand a wide range of pHlevels without rapid deterioration that is between 50 μm and 100 μmthick and may comprise 20% to 35% of the mass of the finished particle.

The resulting particle is finished by sizing through shear mixers in apartial vacuum to have a size, shape, and surface area effective topermit easy pressing as tablets and filling in capsules, gel caps andother oral delivery systems that is no larger than 800 μm in diameter.

d. Method of Manufacture:

Seed granule and the first layer are manufactured in an apparatusdesigned for damp agglomeration and rapid drying of particulatematerial. The apparatus comprises an agglomerator for mixing andforming, over a period of several hours, the requisite materials withdiffuse water to form a damp granular material, discharging the dampgranular material (less than 40% moisture content) through a rotaryblade assembly that repeatedly impacts and cuts the mixture to beagglomerated which is forced out radially through the blade assemblyunder centrifugal and vacuum pressure toward an annular screen. When thedamp granules meet a predetermined size or smaller, they move into adryer apparatus with baffle defining a spiral path through which thegranule exits dry with a carefully adjusted moisture content. Thisprocess is referred to as “damp agglomeration.” The seed granule andfirst layer are manufactured together in the damp agglomerationapparatus under ambient temperature so the damp granule enters therotary blade assembly with a moisture content less than 25%. The firstlayer is applied at the later stage of the mixing process at the samemoisture content as the damp granules. The first layer integrates withthe seed granule as it is forced through the blade assembly undercentrifugal and vacuum pressure toward an annular screen and dried. Theselection of a Type 1 or Type 2 seed granule depends on fat solubleantioxidant (“FSA”) and reactive characteristics of the FSA.

One method of applying the second layer (containing the fat solubleantioxidant mixture) is to add the mixture to the last stage of the dampagglomeration process so it enters with less than 20% moisture contentand is processed through the damp agglomeration apparatus with the seedand first layer to exit the damp agglomerator with between 5% and 10%moisture content.

In the alternative, the second layer may be applied over the dried seedgranule with the first layer using a fluid bed coating apparatusoperating in an inert gas atmosphere if the fat soluble antioxidant ROScharacteristics indicate a need for such care. The fat solubleantioxidant is suspended in a non-reactive polysaccharide or polymer geland sprayed into a stream of seed granules with the first layer alreadyapplied. The fat soluble antioxidant coating is immediately dried in thehot gas stream. The spray system may use a sonic vibration technique orother micro-droplet generating system and a continuous recycling processto regulate the thickness of the second layer to complete theapplication of the second layer.

The third layer is applied using two steps. The first step uses the sameprocedure and damp agglomeration apparatus as the Type 1 seed granule toproduce super fine alkaline earth metal granules with alkali metalhydroxides dispersed within fissures and interstitial spaces having afinished moisture content of less than 15%. The second step in applyingthe third layer is accomplished with a fluid bed coating apparatus inwhich Type 1 granules are suspended in a poly saccharide or polymer gelto be spray dried on particles containing the seed, first and secondlayers. If the fat soluble antioxidant ROS characteristics indicatespecial care in needed, the process will be done in an inert gasatmosphere.

The outer layer may be applied to the third layer by adding athermal-sensitive polymer gel to be spray dried on particles containingthe seed, first, second and third layers then heated to harden thethermal-sensitive polymer. The third layer and outer layer may beapplied in one procedure in which a mixture of super fine Type 1granules are mixed with a thermo- sensitive polymer gel and spray driedon particles containing the seed, first and second layers and heated inthe spray dry apparatus to harden the thermal-sensitive polymer.Finished particles are sifted and any particles not passing through a#80 U.S.A. Standard Testing Sieve will be fed through a rotary bladeassembly that repeatedly impacts and cuts the mixture forced outradially through the blade assembly under centrifugal and vacuumpressure toward an annular screen when the particles meet apredetermined size or smaller and into a dryer apparatus if necessary toget meet moisture content requirements for size, shape, and surface areaeffective to permit easy pressing as tablets and filling in capsules,gel caps and other oral delivery systems. An outer coat may be reappliedto the sized particles if significant fracturing occurs during the finalsixing step in manufacturing process.

e. Method(s) of Use:

a. The resulting four layer particles are stored in air and moistureproof containers to be shipped to packaging facilities to be pressedinto tablets or filled into capsules and bottled for use as dietarysupplements or medical foods. The air and moisture proof containers areshipped to packaging facilities to fill air and moisture proof packetsfor use as food additives to be mixed with food or drink prior toconsumption.

b. One embodiment of the invention is a four-layer particle comprisingthe flavonoid diosmin that would pressed into a tablet or filled into acapsule for daily ingestion as a method to alleviate chronic venousinsufficiency or loaded into a water and air proof packet suitable foradding to water or food and ingested daily as a method to alleviatechronic venous insufficiency.

c. Another embodiment of the invention is a four-layer particlecomprising the flavonoid cyanidin that would be pressed into a tablet orfilled into a capsule for daily ingestion as a method to inhibitdevelopment of diabetes and/or obesity and loaded into a water and airproof packet suitable for adding to water or food and ingested daily asa method to inhibit development of diabetes and/or obesity.

In compliance with the statute, the invention described has beendescribed in language more or less specific on structural features. Itshould be understood however, that the invention is not limited to thespecific features shown, since the means and construction shown,comprises the preferred embodiments for putting the invention intoeffect. The invention is therefore claimed in its forms or modificationswithin the legitimate and valid scope of the amended claims,appropriately interpreted under the doctrine of equivalents.

We claim:
 1. An oral formulation for the controlled release of fatsoluble antioxidants made up of particles each particle comprising: a.seed granules each made of calcium carbonate with microscopic fissuresand interstitial spaces formed therein, disposed inside the microscopicfissures and interstitial spaces are microscopic particles of alkalimetal salt, alkali metal hydroxide or other ions; b. a first layer madeof microcrystal line cellulose and croscarmellose sodium surrounding theoutside surface of said seed granules; c. a second layer comprising amixture of a fat soluble antioxidant and polysaccharide or polypeptidebinder or polymer gel get; d. a third layer surrounding said secondlayer, said third layer made of microscopic alkaline earth metal saltparticles mixed with alkali metal hydroxide, microcrystalline cellulose,croscarmellose sodium binders, and a polysaccharide gel or polymer gel;and, e. at least one harden outer gel layer surrounding said thirdlayer.
 2. The oral formulation, as recited in claim 1, wherein each saidseed granule is 100 μm to 500 μm in diameter.
 3. The oral formulation,as: recited in claim 1, wherein said ions are 7% to 10% by weight ofsaid seed granule.
 4. The oral formulation, as recited in claim 1,wherein said second layer is 15 μm to 100 μm thick.
 5. The oralformulation, as recited in claim 2, wherein said second layer is 15 μmto 100 μm thick.
 6. The oral formulation, as recited in claim 1, whereinsaid third layer is made of calcium carbonate.
 7. The oral formulation,as recited in claim 1, wherein said outer gel layer is made ofhydroxypropyl methylcellulose.
 8. The oral formulation, as recited inclaim 1, wherein said particle includes said seed granule being bound toat least one adjacent seed granule with interstitial spaces formedbetween.
 9. The oral formulation, as recited in claim 8, furtherincluding said alkali metal salt crystals located in said interstitialspaces.
 10. A method for increasing the amount of oral absorption offlavonoid into an animal, comprising the following steps: a. selectingan oral formulation comprising a plurality of seed granules each madecalcium carbonate with microscopic fissures formed thereon, disposedinside the microscopic fissures and interstitial spaces are microscopicparticles of alkali metal salt, alkali metal hydroxide or other ions,forming a first layer made of microcrystalline cellulose orcroscarmellose sodium surrounding the outside surface of said seedgranules; forming a second layer comprising a mixture of a flavonoid andpolysaccharide or polypeptide binder or polymer get, forming a thirdlayer surrounding said second layer, said third layer made ofmicroscopic alkaline earth metal salt particles, and forming a at leastone harden outer gel layer surrounding said third layer; and, b. orallyconsuming said oral formulation.